Migraine, one of the most common neurological disorders in the U.S., is ranked among the top 20 causes of disability worldwide. Migraine is currently one of the leading causes of disease burden for women aged 15-44 years and affects an estimated 11% of the adult population globally, with a strong female predominance. Current approaches to therapy are primarily medication-based but are limited by often- inadequate effectiveness, high costs for many migraine-specific medications, and common side effects. In addition, there likely exist subtypes of migraine that may affect the likelihood of response to treatment, but these have been poorly investigated to-date. Furthermore, many patients are interested in exploring alternatives to pharmacological therapy for this functional disorder. Mindfulness-based stress reduction (MBSR), a meditation-based intervention developed by Kabat-Zinn at the University of Massachusetts, has been increasingly shown to be effective for many patients with a variety of functional disorders. Recent small pilot studies suggest that MBSR may also provide an important benefit as an adjunctive therapy for patients with migraine headaches. In this application, we propose to address these knowledge gaps through a large-scale, multi- component study centered around a Phase III randomized clinical trial of MBSR for patients with moderate-to- severe migraine headache. We will first identify a large number of migraineurs in the Northern California-based Sutter Health system using analytic tools previously developed by our group. Next, using latent class analysis, we will identify subgroups of migraine patients defined by comorbidities. We will then enroll 250 patients with a pattern of 4-14 headaches per month and randomize them to a full MBSR intervention with usual care or usual care alone, with follow-up at 4, 8, and 12 months post-randomization. The primary outcome is change in headache frequency at 4 months; with several secondary outcomes measured at all time points, including assessments of pain, disability, quality of life, mood, and sleep quality. The results of this innovative study will provide valuable information for patients and clinicians seeking to improve the clinical care and patient outcomes for migraineurs.